The biochemical basis for cognitive decline in human immunodeficiency virus type one (HIV-1)-associated dementia (HAD) is a selective and sometimes reversible neuronal impairment caused, in measure, by brain mononuclear phagocyte (MP) infection and immune activation. The mechanism(s) for how HIV-1-infected brain MP alter neural physiological processes (e.g., modulation of synaptic transmission and plasticity) and lead to neural dysfunction during HAD is the focus of this proposal. Electrophysiological, pharmacological, immunological, and molecular techniques will be directed toward 3 specific aims including: (1) the determination of the relative contribution of viral (HIV-1ADA) and cellular (MP-derived) secretory factors to affect neural physiology; (2) the identification of neural receptor subtypes [e.g., N-methyl-D-aspartate] as a common mechanism for MP neurotoxicity; (3) the mechanisms for alterations in cellular and synaptic function will be sought in an animal model of HIV-1-encephalitis. These works, in toto, serve to cross-validate one another by providing both laboratory and animal model study neurophysiological paradigms for disease. Overall, these studies would provide a greater insight into the role(s) that MP-secreted factors play in HAD and the mechanisms underlying lentiviral neuropathogenesis. Moreover, such investigations could allow new opportunities for new drug interventions in a disease that remains a critical source of morbidity and mortality in the infected host.